RESUMO
Leishmaniasis is a neglected tropical parasitic disease with few approved medications. Cutaneous leishmaniasis (CL) is the most frequent form, responsible for 0.7 - 1.0 million new cases annually worldwide. Leukotrienes are lipid mediators of inflammation produced in response to cell damage or infection. They are subdivided into leukotriene B4 (LTB4) and cysteinyl leukotrienes LTC4 and LTD4 (Cys-LTs), depending on the enzyme responsible for their production. Recently, we showed that LTB4 could be a target for purinergic signaling controlling Leishmania amazonensis infection; however, the importance of Cys-LTs in the resolution of infection remained unknown. Mice infected with L. amazonensis are a model of CL infection and drug screening. We found that Cys-LTs control L. amazonensis infection in susceptible (BALB/c) and resistant (C57BL/6) mouse strains. In vitro, Cys-LTs significantly diminished the L. amazonensis infection index in peritoneal macrophages of BALB/c and C57BL/6 mice. In vivo, intralesional treatment with Cys-LTs reduced the lesion size and parasite loads in the infected footpads of C57BL/6 mice. The anti-leishmanial role of Cys-LTs depended on the purinergic P2X7 receptor, as infected cells lacking the receptor did not produce Cys-LTs in response to ATP. These findings suggest the therapeutic potential of LTB4 and Cys-LTs for CL treatment.
Assuntos
Leishmaniose Cutânea , Leishmaniose , Camundongos , Animais , Camundongos Endogâmicos C57BL , Leucotrienos/fisiologia , Leishmaniose Cutânea/tratamento farmacológico , Cisteína , Leucotrieno B4 , Leishmaniose/patologiaRESUMO
Bone metabolism and repair are directly regulated by arachidonic acid metabolites. At present, we analyzed the dose-response effects of a selective cysteinyl leukotriene receptor type-1 antagonist during bone repair after tooth extraction and on non-injured skeleton. Sixty-three 129 Sv/Ev male mice composed the groups: C-Control (saline solution); MTK2-2 mg/Kg of Montelukast (MTK) and MTK4-4 mg/Kg of MTK, daily administered by mouth throughout all experimental periods set at 7, 14, and 21 days post-operative. Dental sockets were analyzed by computed microtomography (microCT), histopathology, and immunohistochemistry. Femurs, L5 vertebra and organs were also removed for observation. Blood was collected for plasma bone and liver markers. Histopathology and microCT analysis revealed early socket repair of MTK2 and MTK4 animals, with significant increased BV/TV at days 14 and 21 compared to C. Higher plasma calcium was detected at days 7 and 21 in MTK4 in comparison to C, while phosphate was significantly increased in MTK2 in the same periods in comparison to C and MTK4. No significant differences were found regarding plasma ALP and TRAP, neither for local TRAP and Runx2 immunolabeling at the healing sockets. Organs did not present histological abnormalities. Increased AST levels have been detected in distinct groups and periods. In general, femur phenotype was improved in MTK treated animals. Collectively, MTK promoted early bone formation after tooth extraction and increased bone quality of femurs and vertebra in a time-dose-dependent manner, and should be considered as an alternative therapy when improved post-extraction socket repair or skeleton preservation is required.